KIM-1 (Kidney Injury Molecule-1) is a type I cell membrane glycoprotein (Ichimura et al., 1998, J. Biol. Chem. 273:4135-4142). The extracellular portion (ectodomain) of KIM-1 contains a six-cysteine immunoglobulin-like domain and a T/SP rich domain characteristic of mucin-like O-glycosylated proteins. The mucin domain extends the Ig-like domain away from the cell surface like a stalk (Jentoft, 1990, Trends Biochem. Sci. 15:291-294). KIM-1 has been identified as the receptor for hepatitis A virus Kaplan et al., 1996, EMBO J. 15:4282-4296; WO 96/04376; U.S. Pat. No. 5,622,861). Two human KIM-1 splice variants have been discovered, with one being predominant in the liver (Feigelstock, 1998, J. Virol. 72:6621-6628), and the other being predominant in the kidney (Ichimura et al., supra).
KIM-1 is a member of a gene family known as the TIM (T cell Immunoglobulin and Mucin domain) family. In addition to KIM-1, there are at least two other members of the TIM family in humans. One member was cloned and originally designated the “200 gene” (WO200073498), but subsequently came to be known as TIM-3. Another member was cloned and designated “gene 58” (WO99/38881).
KIM-1 has attracted interest as a clinical diagnostic marker for kidney damage (Bailly et al., 2002, J. Biol. Chem. 277:39739-39748; Han et al., 2002, Kidney Intl. 62:237-244). A mouse homolog of KIM-1 (TIM-1) has been reported to exist within a genetic locus thought to be involved in the development of airway hyperreactivity (McIntire et al., 2001, Nature Immunology 2:1109). A mouse protein known as TIM-2 has been reported to play a role in the in vivo generation of antigen-specific T cells (Kumanogoh et al., 2002, Nature 419:629-633). A mouse protein known as TIM-3 has been associated with immune response regulation in mice (Monney et al., 2002. Nature 415:536-541).